DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group II, claims 5-14, 19-20, 22, 25-29, and 32-33, in the reply filed on 12/22/2025 is acknowledged.
Priority
Priority to 63/021,179, filed 5/7/2020, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) was submitted on 11/4/2022 before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 5-16, 19-20, 22, 25-29, 32-35, 38, and 40-43 are currently pending. Claims 5-16, 19-20, 22, 25-29, 32-35, 38, and 40-43 are under examination.
Claim Interpretation
Claims 34, 35, and 38 recite a list of elements with the last element listed following “and/or”. This can be interpreted as the “and/or” applies to each element or only the last element.
For purposes of examination, the broadest reasonable interpretation is that the entire list of elements is construed in the alternative.
Claim Objections
Claims 5, 6, 7, and 10 are objected to because each contains redundant and superfluous language that fails to meaningfully limit the pending claim scope. Specifically, these claims recite the phrase “comprising at least 80%, at least 81%, at least 82%, at least 83%, at least 84%,at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to” one or more sequences, but only the recitation of “at least 80%” is limiting, because if something satisfies the broadest limitation, then it fully satisfies the entire claim scope, and if something satisfies the most stringent limitation (e.g., 100%”) then it necessarily and inherently must also satisfies the broader limitation (e.g., if something is 100% identical, it is also at least 80% identical). Accordingly, such limitations within the same claim are non-limiting and superfluous. Redundant and superfluous language should be removed to enhance claim clarity and to minimize potential confusion.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 5, 8, and 15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to natural phenomenon without significantly more. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the following reasons. This judicial exception is not integrated into a practical application because the peptide being claimed is naturally occurring. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because for the following reasons.
Step 1: The instant claims are directed to a statutory patent-eligible subject matter category, a composition of matter.
Step 2a, Prong 1: The claims are directed to a natural phenomenon, specifically a natural-based product limitation.
Specifically, Uniprot Accession No: A0A2Y9P5P3 is aligned against Applicant SEQ ID NO: 4 below:
# Aligned_sequences: 2
# 1: EMBOSS_001
# 2: EMBOSS_001
# Matrix: EBLOSUM62
# Gap_penalty: 10.0
# Extend_penalty: 0.5
#
# Length: 310
# Identity: 275/310 (88.7%)
# Similarity: 288/310 (92.9%)
# Gaps: 0/310 ( 0.0%)
# Score: 1465.0
#
#
#=======================================
EMBOSS_001 1 MPPLRIVPSRLLSQLYCGLKPPASIQTKICLTMARPSSSMADFRKCFAKA 50
|.||:||||||:||||||||||||.:.:|||.|||||||||||||.||||
EMBOSS_001 1 MRPLQIVPSRLISQLYCGLKPPASTRNQICLKMARPSSSMADFRKFFAKA 50
EMBOSS_001 51 KHIVIISGAGVSAESGVPTFRGAGGYWRRWKAQDLATPQAFARNPSQVWE 100
||||||||||||||||||||||||||||||:|||||||.|||.|||:|||
EMBOSS_001 51 KHIVIISGAGVSAESGVPTFRGAGGYWRRWQAQDLATPLAFAHNPSRVWE 100
EMBOSS_001 101 FYHYRREVVQSKEPNAGHLAIA ECEARLGRQGRRVTVITQNIDELHRKAG 150
||||||||:.|:||||||.||||||.|||:|||||.|||||||||||:||
EMBOSS_001 101 FYHYRREVMGSREPNAGHRAIA ECETRLGKQGRRVVVITQNIDELHRRAG 150
EMBOSS_001 151 TKNLLEIHGSLFKTRCTSCGVVAENYKSPICPALSGKGAPEPETQDARIP 200
|:||||||||||||||||||||||||||||||||||||||||.||||.||
EMBOSS_001 151 TRNLLEIHGSLFKTRCTSCGVVAENYKSPICPALSGKGAPEPGTQDASIP 200
EMBOSS_001 201 VEKLPRCEEAACGGLLRPHVVWFGENLDPAILEEAGRELALCDLCLVVGT 250
||||||||||.|||||||||||||||||||||||..||||.|||||||||
EMBOSS_001 201 VEKLPRCEEAGCGGLLRPHVVWFGENLDPAILEEVDRELAHCDLCLVVGT 250
EMBOSS_001 251 SSVVYPAAMFAPEVSARGVPVAEFNIEATPAANRFRFHFQGPCGTTLPEA 300
||||||||||||:|:||||||||||.|.|||.||||||||||||||||||
EMBOSS_001 251 SSVVYPAAMFAPQVAARGVPVAEFNTETTPATNRFRFHFQGPCGTTLPEA 300
EMBOSS_001 301 LAPHETETVS 310
||.||.||||
EMBOSS_001 301 LACHENETVS 310
This sequence has 88.7% identity with Applicant SEQ ID NO: 4, and position 79 is an arginine. Uniprot Accession No: A0A2Y9P5P3 is a naturally-occurring protein from Delphinapterus leucas (Beluga whale) (UniProt, A0A2Y9P5P3 entry, published 9/12/2018, accessed 3/2/2026). The Beluga Whale necessarily possess a nucleic acid which codes for the protein disclosed above. Therefore, the nucleic acid of claim 5 is a natural product.
Step 2a, Prong 2: The claims are integrated into practical application. This judicial exception is not integrated into a practical application because the nucleic acid being claimed is naturally occurring.
Step 2b: The claims, as a whole, do not recite any additional elements that amount to significantly more than the judicial exception. Specifically, the claims do not include any elements in addition to the natural product.
Regarding claim 8, the Beluga Whale gene would also have a promoter. Consequently, claim 8 is rejected.
Regarding claim 15, water, which is a naturally occurring substance, may serve as a pharmaceutically acceptable carrier. Consequently, claim 15 is rejected.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 19, 20, 22, 25- 29, 32, and 33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 5 recites an isolated nucleic acid that encodes a mutant SIRT5 protein at least 80% identical to SEQ ID NO: 4 or SEQ ID NO: 10, wherein the protein retains arginine at one or more positions 79, 112, 148, 152 of SEQ ID NO: 4 or SEQ ID NO: 10. This claim encompasses an enormous sequence space. As an approximation, the protein encoded is 310 amino acids in length. Allowing 20% variance gives 62 possible mutations. Ignoring position of mutations, this yields 20^62 possible proteins. The nucleic acid sequences encoding these proteins are degenerate, but would still be within a few factors of 20^62.
In this case, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. (MPEP § 2163 (II.A.3.a.ii.))
According to MPEP § 2163 (II.A.3.a.ii.), a "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
As described above, claim 5, and therefore claim 19, recites extremely large genus of nucleic acids.
MPEP § 2163 (II.A.3.a.ii.) states that “for inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’”
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus.
In the instant case, Applicant reduces two sequences to practice: SEQ ID NO: 4 and SEQ ID NO: 10. At the time the invention was made, the level of skill for preparing peptides (and encoding nucleic acids) with desired functional properties was high. However, even if a synthesis and selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify that yield polypeptides with the recited properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure provided by the provided species, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what peptide (and encoding nucleic acids) with a particular set of properties would look like structurally. Therefore, the provided examples only represent a limited structural diversity.
Since only a limited number of species of peptides are taught within the claimed genus above, the instant claim above fails the written description requirement. A representative number of species has not been taught to describe this genus. Regarding the peptides, a single point mutation can change the biophysical properties of a peptide: “In summary, we have shown that the structural changes in the fibrillar state of the Aβ42 peptide that are observed to occur upon introduction of single point mutations can be accompanied by changes in the dominance of the microscopic processes by which these aggregates are themselves formed.” (Bolognesi et al. ACS Chem Bio 9:2 (2013) page 381 col. 2 para. 3) and “In summary, while ovispirin-1 and novispirin G-10 both had solution structures that were helical and amphipathic in the presence of TFE, a relatively simple change in their primary structure (a single glycine–isoleucine exchange) had profound effects on their respective toxicities for human erythrocytes and epithelial cells.” (Sawai et al. Protein Eng. 15:3 (2002) page 232 col. 1 para. 3).
Furthermore, many sequences allowed by the current scope of the claims, result in non-functional aggregates. Wang (Wang, et al. MAbs. Vol. 1. No. 3. Taylor & Francis, (2009)) discloses a variety of aggregation prone motifs that occur in commercial antibodies (Wang, page 262, Table 2). The scope of the claims currently may incorporate such motifs and result in non-functional aggregates.
Given this unpredictability of protein design, the skilled artisan would not have been in possession of the substantial repertoire of peptide species encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of every peptide molecule recited by claim 17. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus. Therefore, claim 19 is rejected.
Regarding claim 20, claim 20 has the same scope of claimed nucleic acids because claim 20 also depends on claim 5. Claim 20 does not reduce the scope of the claimed genus, therefore, claim 20 is rejected.
Regarding claims 22, 25- 29, 32, and 33, these claims all retain the same claim scope of claim 20. Claims 22, 25-29, 32, and 33 are rejected.
Claims 19, 20, 25-29, 32, and 33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of an organic acidemia that results in the methylmalonylation or malonylation, a vitamin B12 deficiency, or a metabolic disorder that results in the methylmalonylation or malonylation with the proteins encoded by SEQ ID NO: 4 and SEQ ID NO: 10, does not reasonably provide enablement for the treatment of any possible metabolic disorder with the full range of proteins encoded by the claimed nucleic acids of claim 5. Furthermore, the specification is not enabling for treating disorders resulting from propionylation. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024). These factors include, but are not limited to:
The breadth of the claims;
Claim 19 is extremely broad in two ways. First, the proteins resulting from the claimed nucleic acid are extremely broad. Second, any possible metabolic disorder is also extremely broad.
The nature of the invention;
The invention is a method of treating an organic acidemia (OA), vitamin B 12 deficiency, or metabolic disorder.
The state of the prior art;
Regarding metabolic disease, Metabolic disease (Encyclopedia Britannica, accessed 2/12/2020 at URL: britannica.com/science/metabolic-disease; pp. 1-17 (2019)) defines a metabolic disease as any of the diseases or disorders that disrupt normal metabolism, the process of converting food to energy on a cellular level. Thousands of enzymes participating in numerous interdependent metabolic pathways carry out this process (Encyclopedia Britannica, page 1, para. 1). Metabolic diseases affect the ability of the cell to perform critical biochemical reactions that involve the processing or transport of proteins (amino acids), carbohydrates (sugars and starches), or lipids (fatty acids). Id. Metabolic diseases are typically hereditary, yet most persons affected by them may appear healthy for days, months, or even years. The onset of symptoms usually occurs when the body's metabolism comes under stress-for example, after prolonged fasting or during a febrile illness. For some metabolic disorders, it is possible to obtain prenatal diagnostic screening. (Encyclopedia Britannica, page 1, para. 2)
Food is broken down in a series of steps by cellular enzymes (proteins that catalyze the conversion of compounds called substrates) into products with a different biochemical structure. These products then become the substrate for the next enzyme in a metabolic pathway (Encyclopedia Britannica, page 3, para. 1). If an enzyme is missing or has diminished activity, the pathway becomes blocked, and the formation of the final product is deficient, resulting in disease (Encyclopedia Britannica, page 3, para. 1). Low activity of an enzyme may result in the subsequent accumulation of the enzyme's substrate, which may be toxic at high levels. In addition, minor metabolic pathways that usually lie dormant may be activated when a substrate accumulates, possibly forming atypical, potentially toxic, products. Each cell in the body contains thousands of metabolic pathways (Encyclopedia Britannica, page 3, para. 1).
Metabolic disorders can include, but are not limited to, disorders of amino acid metabolism, urea cycle defects, amino acid transport disorders, organic acidemias, disorders of carbohydrate metabolism, disorders of lipid metabolism, mitochondrial disorders, lysosomal storage disorders, peroxisomal disorders, purine and pyrimidine disorders, porphyrias (Encyclopedia Britannica, pages 5-12).
Cornier et al. (Cornier, et al. Endocrine reviews 29.7: 777-822 (2008)) is a review article discussing metabolic syndrome. Metabolic syndrome (MetS) is a clustering of components that reflect over-nutrition, sedentary lifestyles, and resultant excess adiposity. The MetS includes the clustering of abdominal obesity, insulin resistance, dyslipidemia, and elevated blood pressure and is associated with other comorbidities including the prothrombotic state, proinflammatory state, nonalcoholic fatty liver disease, and reproductive disorders (abstract). MetS is not a single disease. Id. Treatment of MetS involves lifestyle modification (diet, exercise) and treatment for underlying/associated conditions, e.g., diabetes, weight loss, high blood pressure, and dyslipidemia (Cornier et al., pages 797-803).
Regarding Vitamin B12, deficiency, Morel et al. (Morel, et al. Molecular genetics and metabolism 86.1-2: 160-171 (2005)) discloses that:
“Vitamin B12 (cobalamin, Cbl), in the form of thecofactors methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl), is required by the cytoplasmic enzyme
methionine synthase (MS) and by the mitochondrial enzyme methylmalonyl-CoA mutase (mut), respectively. Inherited disorders of intracellular Cbl metabolism are
rare conditions and have been classified on the basis of somatic cell complementation as belonging to eight different mutant groups (cblA to cblH) [1,2]. Methylmalonic
aciduria due to methylmalonyl-CoA mutase deficiency makes up an additional complementation group (mut) [3,4]. Functional deWciencies of MS lead to homocystinuria and elevated total plasma homocysteine (cblE,
cblG, and cblD variant 1), while functional mutase deficiencies lead to methylmalonic aciduria (cblA, cblB, cblD variant 2, cblH and mut deficiency) (Morel et al., page 160, col. 1, para. 1). Therefore, B12 deficiency results in methylmalonic aciduria, a condition which the present invention is enabled to treat.
The level of one of ordinary skill;
A person of ordinary skill in the art typically would possess at least a Master’s level education and frequently a Ph.D.
The level of predictability in the art;
Protein-protein interactions are very unpredictable in general. A single point mutation can change the biophysical properties of a peptide: “In summary, we have shown that the structural changes in the fibrillar state of the Aβ42 peptide that are observed to occur upon introduction of single point mutations can be accompanied by changes in the dominance of the microscopic processes by which these aggregates are themselves formed.” (Bolognesi et al. ACS Chem Bio 9:2 (2013) page 381 col. 2 para. 3) and “In summary, while ovispirin-1 and novispirin G-10 both had solution structures that were helical and amphipathic in the presence of TFE, a relatively simple change in their primary structure (a single glycine–isoleucine exchange) had profound effects on their respective toxicities for human erythrocytes and epithelial cells.” (Sawai et al. Protein Eng. 15:3 (2002) page 232 col. 1 para. 3).
Furthermore, many sequences allowed by the current scope of the claims, result in non-functional aggregates. Wang (Wang, et al. MAbs. Vol. 1. No. 3. Taylor & Francis, (2009)) discloses a variety of aggregation prone motifs that occur in commercial antibodies (Wang, page 262, Table 2). The scope of the claims currently may incorporate such motifs and result in non-functional aggregates.
(F) The amount of direction provided by the inventor and the existence of working examples and the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Applicant reduces SEQ ID NO: 4 and SEQ ID NO: 11 to practice. The data for diacylation activity and treatment of MMA mice with these constructs is robust, but limited to two sequences.
Regarding claim 19, claim 19 recites a method of treating an organic acidemia (OA), vitamin B 12 deficiency, or metabolic disorder, comprising: administering a therapeutically effective amount of the nucleic acid molecule of claim 5 to a subject having an OA, vitamin B 12 deficiency, or metabolic disorder, thereby treating the OA, vitamin B 12 deficiency, or metabolic disorder. Regarding propionylation, the specification discloses that the claimed SIRT5 mutant does not affect propionylation in vivo. (Specification, page 9, line 4)
It would require undue experimentation for a person of ordinary skill in the art to test all the molecules encompassed by claim 5 against all possible metabolic disorders and any organic acidemias not involving methylmalonylation or malonylation to check for efficacy. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claim 19 is rejected.
Regarding claim 20, claim 20 recites a method of treating an organic acidemia (OA), vitamin B 12 deficiency, or metabolic disorder, comprising: detecting one or more proteins posttranslationally modified with methylmalonyllation in a sample from a subject having or suspected of having an OA, vitamin B 12 deficiency, or metabolic disorder; and administering a therapeutically effective amount of the nucleic acid molecule of claim 5 to the subject having or suspected of having the OA, vitamin B 12 deficiency, or metabolic disorder, thereby treating the OA, vitamin B 12 deficiency, or metabolic disorder.
Claim 20 has the same scope as claim 19 with respect to metabolic disorders, organic acidemia, and the nucleic acids of claim 5. It would require undue experimentation for a person of ordinary skill in the art to test all the molecules encompassed by claim 5 against all possible metabolic disorders and any organic acidemias not involving methylmalonylation or malonylation to check for efficacy. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claim 20 is rejected.
Regarding claim 25, Mitchell et al. (Mitchell et al. Molecular genetics and metabolism 94.1: 4-15 (2008)) discloses that those types of organic acidemias cause problems with Acetyl-CoA metabolism, and therefore those OAs are enabled by the present specification (Mitchell et al., page 6, Table I).
However, the scope issues with all possible metabolic disorders and the nucleic acids of claim 5 remain.
Claim 25 is rejected.
Regarding claims 26-29 and claim 32, these claims have the same scope issues with all possible metabolic disorders and the nucleic acids of claim 5.
Claims 26-29 and 32 are rejected.
Regarding claim 33, Mitchell et al. (Mitchell et al. Molecular genetics and metabolism 94.1: 4-15 (2008)) discloses that those types of organic acidemias cause problems with Acetyl-CoA metabolism, and therefore those OAs are enabled by the present specification (Mitchell et al., page 6, Table I).
However, the scope issues with all the nucleic acids of claim 5 and any possible organic acidemia remain.
Claim 33 is rejected.
Claim 22 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for reducing PTMs in a subject having an organic acidemia that results in the methylmalonylation or malonylation, a vitamin B12 deficiency, a metabolic disorder that results in the methylmalonylation or malonylation, or reducing blood ammonia by at least 10% in a subject having an organic acidemia that results in the methylmalonylation or malonylation with the proteins encoded by SEQ ID NO: 4 and SEQ ID NO: 10, does not reasonably provide enablement for reducing PTMs or caused by any possible metabolic disorder with the full range of proteins encoded by the claimed nucleic acids of claim 5, or reducing blood ammonia by at least 10% in a subject with any possible organic acedmia. The specification is also not enabled for reducing blood glycine or urine glycine by at least 10% in a subject. Furthermore, the specification is not enabling for treating disorders resulting from propionylation. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024). These factors include, but are not limited to:
The breadth of the claims;
Claim 22 is extremely broad in two ways. First, the proteins resulting from the claimed nucleic acid are extremely broad. Second, any possible metabolic disorder is also extremely broad.
The nature of the invention;
The invention is a method of treating an organic acidemia (OA), vitamin B 12 deficiency, or metabolic disorder.
The state of the prior art;
Regarding metabolic disease, Metabolic disease (Encyclopedia Britannica, accessed 2/12/2020 at URL: britannica.com/science/metabolic-disease; pp. 1-17 (2019)) defines a metabolic disease as any of the diseases or disorders that disrupt normal metabolism, the process of converting food to energy on a cellular level. Thousands of enzymes participating in numerous interdependent metabolic pathways carry out this process (Encyclopedia Britannica, page 1, para. 1). Metabolic diseases affect the ability of the cell to perform critical biochemical reactions that involve the processing or transport of proteins (amino acids), carbohydrates (sugars and starches), or lipids (fatty acids). Id. Metabolic diseases are typically hereditary, yet most persons affected by them may appear healthy for days, months, or even years. The onset of symptoms usually occurs when the body's metabolism comes under stress-for example, after prolonged fasting or during a febrile illness. For some metabolic disorders, it is possible to obtain prenatal diagnostic screening. (Encyclopedia Britannica, page 1, para. 2)
Food is broken down in a series of steps by cellular enzymes (proteins that catalyze the conversion of compounds called substrates) into products with a different biochemical structure. These products then become the substrate for the next enzyme in a metabolic pathway (Encyclopedia Britannica, page 3, para. 1). If an enzyme is missing or has diminished activity, the pathway becomes blocked, and the formation of the final product is deficient, resulting in disease (Encyclopedia Britannica, page 3, para. 1). Low activity of an enzyme may result in the subsequent accumulation of the enzyme's substrate, which may be toxic at high levels. In addition, minor metabolic pathways that usually lie dormant may be activated when a substrate accumulates, possibly forming atypical, potentially toxic, products. Each cell in the body contains thousands of metabolic pathways (Encyclopedia Britannica, page 3, para. 1).
Metabolic disorders can include, but are not limited to, disorders of amino acid metabolism, urea cycle defects, amino acid transport disorders, organic acidemias, disorders of carbohydrate metabolism, disorders of lipid metabolism, mitochondrial disorders, lysosomal storage disorders, peroxisomal disorders, purine and pyrimidine disorders, porphyrias (Encyclopedia Britannica, pages 5-12).
Cornier et al. (Cornier, et al. Endocrine reviews 29.7: 777-822 (2008)) is a review article discussing metabolic syndrome. Metabolic syndrome (MetS) is a clustering of components that reflect over-nutrition, sedentary lifestyles, and resultant excess adiposity. The MetS includes the clustering of abdominal obesity, insulin resistance, dyslipidemia, and elevated blood pressure and is associated with other comorbidities including the prothrombotic state, proinflammatory state, nonalcoholic fatty liver disease, and reproductive disorders (abstract). MetS is not a single disease. Id. Treatment of MetS involves lifestyle modification (diet, exercise) and treatment for underlying/associated conditions, e.g., diabetes, weight loss, high blood pressure, and dyslipidemia (Cornier et al., pages 797-803).
Regarding Vitamin B12, deficiency, Morel et al. (Morel, et al. Molecular genetics and metabolism 86.1-2: 160-171 (2005)) discloses that:
“Vitamin B12 (cobalamin, Cbl), in the form of thecofactors methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl), is required by the cytoplasmic enzyme
methionine synthase (MS) and by the mitochondrial enzyme methylmalonyl-CoA mutase (mut), respectively. Inherited disorders of intracellular Cbl metabolism are
rare conditions and have been classified on the basis of somatic cell complementation as belonging to eight different mutant groups (cblA to cblH) [1,2]. Methylmalonic
aciduria due to methylmalonyl-CoA mutase deficiency makes up an additional complementation group (mut) [3,4]. Functional deWciencies of MS lead to homocystinuria and elevated total plasma homocysteine (cblE,
cblG, and cblD variant 1), while functional mutase deficiencies lead to methylmalonic aciduria (cblA, cblB, cblD variant 2, cblH and mut deficiency) (Morel et al., page 160, col. 1, para. 1). Therefore, B12 deficiency results in methylmalonic aciduria, a condition which the present invention is enabled to treat.
The level of one of ordinary skill;
A person of ordinary skill in the art typically would possess at least a Master’s level education and frequently a Ph.D.
The level of predictability in the art;
Protein-protein interactions are very unpredictable in general. A single point mutation can change the biophysical properties of a peptide: “In summary, we have shown that the structural changes in the fibrillar state of the Aβ42 peptide that are observed to occur upon introduction of single point mutations can be accompanied by changes in the dominance of the microscopic processes by which these aggregates are themselves formed.” (Bolognesi et al. ACS Chem Bio 9:2 (2013) page 381 col. 2 para. 3) and “In summary, while ovispirin-1 and novispirin G-10 both had solution structures that were helical and amphipathic in the presence of TFE, a relatively simple change in their primary structure (a single glycine–isoleucine exchange) had profound effects on their respective toxicities for human erythrocytes and epithelial cells.” (Sawai et al. Protein Eng. 15:3 (2002) page 232 col. 1 para. 3).
Furthermore, many sequences allowed by the current scope of the claims, result in non-functional aggregates. Wang (Wang, et al. MAbs. Vol. 1. No. 3. Taylor & Francis, (2009)) discloses a variety of aggregation prone motifs that occur in commercial antibodies (Wang, page 262, Table 2). The scope of the claims currently may incorporate such motifs and result in non-functional aggregates.
(F) The amount of direction provided by the inventor and the existence of working examples and the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Applicant reduces SEQ ID NO: 4 and SEQ ID NO: 11 to practice. The data for diacylation activity and treatment of MMA mice with these constructs is robust, but limited to two sequences.
Regarding claim 22, claim 22 recites a method of reducing post-translational modifications (PTMs) of proteins in a subject having an OA, vitamin B 12 deficiency, or metabolic disorder, or a method of reducing blood glycine and/or urine glycine by at least 10% in a subject having an OA, or a method of reducing blood ammonia by at least 10% in a subject having an OA, comprising: administering a therapeutically effective amount the nucleic acid molecule of claim 5 to the subject having the OA, vitamin B 12 deficiency, or metabolic disorder, thereby reducing PTMs of proteins in the subject having OA, a vitamin B 12 deficiency, or metabolic disorder, or reducing blood and/or urine glycine by at least 10% in the subject having OA, or reducing blood ammonia by at least 10% in the subject having OA.
Regarding propionylation, the specification discloses that the claimed SIRT5 mutant does not affect propionylation in vivo (Specification, page 9, line 4). Furthermore, no data is provided for blood glycine or urine glycine reduction.
It would require undue experimentation for a person of ordinary skill in the art to test all the molecules encompassed by claim 5 against all possible metabolic disorders and any organic acidemias not involving methylmalonylation or malonylation to check for efficacy. It would also require undue experimentation to test all claimed molecules for glycine reduction efficacy. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claim 22 is rejected.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 34, 35, and 38 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gerbanowski e et al. (Gerbanowski, A., et al. Journal of protein chemistry 18.3: 325-336 (1999)).
Regarding claim 34, the elements of claim 34 are interpreted to be claimed in the alternative as described above. Gerbanowski discloses the acylation of bovine serum albumin: “Bovine serum albumin was chosen as a model protein to study the effect of the functionalization of the ε-NH2 of lysine residues with different carbon chains on the physical properties of proteins. Thus, BSA has been acylated and sulfonylated by means of anhydrides and sulfonyl chlorides, respectively.” (Gerbanowski et al., page 325, Abstract).
Consequently, claim 34 is anticipated by Berbanowski et al. and rejected.
Regarding claim 35, claim 34 is anticipated as discussed above. Claim 35 further recites the case wherein the acylated protein is bovine serum albumin. Gerbanowski discloses the acylation of bovine serum albumin: “Bovine serum albumin was chosen as a model protein to study the effect of the functionalization of the ε-NH2 of lysine residues with different carbon chains on the physical properties of proteins. Thus, BSA has been acylated and sulfonylated by means of anhydrides and sulfonyl chlorides, respectively.” (Gerbanowski et al., page 325, Abstract).
Consequently, claim 35 is anticipated by Gerbanowski et al. and rejected.
Regarding claim 38, the elements of claim 38 are interpreted to be claimed in the alternative as described above. Claim 34 is anticipated as described above. Claim 38 further recites that the kit further comprises a non-acylated version of the acylated protein.
Gerbanowksi discloses a mixture of acylated and non-acylated bovine serum albumin: “A similar result was observed for hexanoic grafted BSA at a modification rate lower than 35%. For higher acylation percentages increasing to 60% and 95%, the number of hydrophobic sites increased to 9 and 12, respectively.” (Gerbanowski, et al., page 332, col. 2, para. 2, Table IV).
Consequently, claim 38 is anticipated by Gerbanowski et al. and rejected.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 5, 8, 9, 13, 14 are rejected under 35 U.S.C. 103 as being unpatentable over UniProt entry A0A2Y9P5P3, published 9/12/2018, accessed 3/2/2026 over Codon Usage Database, https://www.kazusa.or.jp/codon/cgi-bin/showcodon.cgi?species=4932, published 6/15/2007, accessed 3/2/2026 and Hartley et al. (Hartley, James L. Current Opinion in Biotechnology 17.4: 359-366 (2006)).
Uniprot Accession No: A0A2Y9P5P3 is aligned against Applicant SEQ ID NO: 4 below:
# Aligned_sequences: 2
# 1: EMBOSS_001
# 2: EMBOSS_001
# Matrix: EBLOSUM62
# Gap_penalty: 10.0
# Extend_penalty: 0.5
#
# Length: 310
# Identity: 275/310 (88.7%)
# Similarity: 288/310 (92.9%)
# Gaps: 0/310 ( 0.0%)
# Score: 1465.0
#
#
#=======================================
EMBOSS_001 1 MPPLRIVPSRLLSQLYCGLKPPASIQTKICLTMARPSSSMADFRKCFAKA 50
|.||:||||||:||||||||||||.:.:|||.|||||||||||||.||||
EMBOSS_001 1 MRPLQIVPSRLISQLYCGLKPPASTRNQICLKMARPSSSMADFRKFFAKA 50
EMBOSS_001 51 KHIVIISGAGVSAESGVPTFRGAGGYWRRWKAQDLATPQAFARNPSQVWE 100
||||||||||||||||||||||||||||||:|||||||.|||.|||:|||
EMBOSS_001 51 KHIVIISGAGVSAESGVPTFRGAGGYWRRWQAQDLATPLAFAHNPSRVWE 100
EMBOSS_001 101 FYHYRREVVQSKEPNAGHLAIA ECEARLGRQGRRVTVITQNIDELHRKAG 150
||||||||:.|:||||||.||||||.|||:|||||.|||||||||||:||
EMBOSS_001 101 FYHYRREVMGSREPNAGHRAIA ECETRLGKQGRRVVVITQNIDELHRRAG 150
EMBOSS_001 151 TKNLLEIHGSLFKTRCTSCGVVAENYKSPICPALSGKGAPEPETQDARIP 200
|:||||||||||||||||||||||||||||||||||||||||.||||.||
EMBOSS_001 151 TRNLLEIHGSLFKTRCTSCGVVAENYKSPICPALSGKGAPEPGTQDASIP 200
EMBOSS_001 201 VEKLPRCEEAACGGLLRPHVVWFGENLDPAILEEAGRELALCDLCLVVGT 250
||||||||||.|||||||||||||||||||||||..||||.|||||||||
EMBOSS_001 201 VEKLPRCEEAGCGGLLRPHVVWFGENLDPAILEEVDRELAHCDLCLVVGT 250
EMBOSS_001 251 SSVVYPAAMFAPEVSARGVPVAEFNIEATPAANRFRFHFQGPCGTTLPEA 300
||||||||||||:|:||||||||||.|.|||.||||||||||||||||||
EMBOSS_001 251 SSVVYPAAMFAPQVAARGVPVAEFNTETTPATNRFRFHFQGPCGTTLPEA 300
EMBOSS_001 301 LAPHETETVS 310
||.||.||||
EMBOSS_001 301 LACHENETVS 310
This sequence has 88.7% identity with Applicant SEQ ID NO: 4, and position 79 is an arginine.
Uniprot Accession No: A0A2Y9P5P3 does not disclose a nucleic acid sequence. However, the Codon Usage Database disclose the following codon usage table for Saccharomyces cerevisiae as follows:
AmAcid Codon Number /1000 Fraction ..
Gly GGG 39359.00 6.02 0.00
Gly GGA 71216.00 10.90 0.00
Gly GGT 156109.00 23.89 0.00
Gly GGC 63903.00 9.78 0.00
Glu GAG 125717.00 19.24 0.00
Glu GAA 297944.00 45.60 0.00
Asp GAT 245641.00 37.59 0.00
Asp GAC 132048.00 20.21 0.00
Val GTG 70337.00 10.76 0.00
Val GTA 76927.00 11.77 0.00
Val GTT 144243.00 22.07 0.00
Val GTC 76947.00 11.78 0.00
Ala GCG 40358.00 6.18 0.00
Ala GCA 105910.00 16.21 0.00
Ala GCT 138358.00 21.17 0.00
Ala GCC 82357.00 12.60 0.00
Arg AGG 60289.00 9.23 0.00
Arg AGA 139081.00 21.28 0.00
Ser AGT 92466.00 14.15 0.00
Ser AGC 63726.00 9.75 0.00
Lys AAG 201361.00 30.82 0.00
Lys AAA 273618.00 41.87 0.00
Asn AAT 233124.00 35.68 0.00
Asn AAC 162199.00 24.82 0.00
Met ATG 136805.00 20.94 0.00
Ile ATA 116254.00 17.79 0.00
Ile ATT 196893.00 30.13 0.00
Ile ATC 112176.00 17.17 0.00
Thr ACG 52045.00 7.96 0.00
Thr ACA 116084.00 17.76 0.00
Thr ACT 132522.00 20.28 0.00
Thr ACC 83207.00 12.73 0.00
Trp TGG 67789.00 10.37 0.00
End TGA 4447.00 0.68 0.00
Cys TGT 52903.00 8.10 0.00
Cys TGC 31095.00 4.76 0.00
End TAG 3312.00 0.51 0.00
End TAA 6913.00 1.06 0.00
Tyr TAT 122728.00 18.78 0.00
Tyr TAC 96596.00 14.78 0.00
Leu TTG 177573.00 27.17 0.00
Leu TTA 170884.00 26.15 0.00
Phe TTT 170666.00 26.12 0.00
Phe TTC 120510.00 18.44 0.00
Ser TCG 55951.00 8.56 0.00
Ser TCA 122028.00 18.67 0.00
Ser TCT 153557.00 23.50 0.00
Ser TCC 92923.00 14.22 0.00
Arg CGG 11351.00 1.74 0.00
Arg CGA 19562.00 2.99 0.00
Arg CGT 41791.00 6.40 0.00
Arg CGC 16993.00 2.60 0.00
Gln CAG 79121.00 12.11 0.00
Gln CAA 178251.00 27.28 0.00
His CAT 89007.00 13.62 0.00
His CAC 50785.00 7.77 0.00
Leu CTG 68494.00 10.48 0.00
Leu CTA 87619.00 13.41 0.00
Leu CTT 80076.00 12.25 0.00
Leu CTC 35545.00 5.44 0.00
Pro CCG 34597.00 5.29 0.00
Pro CCA 119641.00 18.31 0.00
Pro CCT 88263.00 13.51 0.00
Pro CCC 44309.00 6.78 0.00
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the codon usage table of the Codon Usage Database to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to use Codon Usage Database to determine a nucleic acid sequence likely to express the desired protein (SEQ ID NO: 4) when cloned into an expression vector as disclosed by Hartley et al. (Hartley et al., page 359, col. 1, para. 1). A person of ordinary skill in the art would have a reasonable expectation of success because Hartley describes this practice as routine: “Few proteins are abundant enough to be isolated from their native hosts. Clearly evolution has adjusted the in vivo level of each protein to match the needs of the cell. The tasks for the scientist who needs a larger amount of a
protein are to contrive ways to increase its production in an appropriate host and to facilitate its purification. Protein overexpression requires three components: a gene, a vector that contains the gene, and an expression host that maximizes the amount and quality of the protein produced by the vector–gene combination.” (Hartley et al., page 359, col. 1, para. 1).
Consequently claim 5 is obvious over UniProt in view of Codon Usage Database and Hartley et al. and rejected.
Regarding claim 8, claim 5 is obvious as described above. Claim 8 further recites the case wherein the isolated nucleic acid further comprises a promoter operably linked to the isolated nucleic acid molecule encoding the protein.
Hartley discloses the usage of promoters: “The first recombinant proteins were overproduced by simply cloning entire DNA segments on multicopy plasmids; that is, the amount of protein was increased by increasing the copy number of the promoter–gene combination. Later on, genes were removed from the influence of their native promoters and inserted downstream of more powerful, inducible promoters.” (Hartley et al., page 359, col. 2, para. 3).
Consequently claim 8 is obvious over UniProt in view of Codon Usage Database and Hartley et al. and rejected.
Regarding claim 9, claim 5 is obvious as described above. Claim 9 further recites the case wherein the isolated nucleic acid is part of a vector. Hartley discloses the usage of vectors with recombinant nucleic acids: “Few proteins are abundant enough to be isolated from their native hosts. Clearly evolution has adjusted the in vivo level of each protein to match the needs of the cell. The tasks for the scientist who needs a larger amount of a
protein are to contrive ways to increase its production in an appropriate host and to facilitate its purification. Protein overexpression requires three components: a gene, a vector that contains the gene, and an expression host that maximizes the amount and quality of the protein produced by the vector–gene combination.” (Hartley et al., page 359, col. 1, para. 1).
Consequently claim 9 is obvious over UniProt in view of Codon Usage Database and Hartley et al. and rejected.
Regarding claim 13, claim 9 is obvious as described above. Claim 13 further recites the case wherein the vector is part of a host cell.
Hartley discloses the usage of host cells: “The required amount, purity, homogeneity, and activity of the protein of interest usually determine the choice of expression context, vector and host. Usually the first consideration is what host cell to use. Expression in Escherichia coli is fast, inexpensive and scaleable, and minimal post-translational modifications make proteins purified from E. coli relatively homogeneous and highly desirable for structural studies.” (Hartley et al., page 359, col. 2, para. 2).
Consequently claim 13 is obvious over UniProt in view of Codon Usage Database and Hartley et al. and rejected.
Regarding claim 14, claim 13 is obvious as described above. Claim 14 further recites the case wherein the host cell is a bacterium, human, or yeast cell.
Hartley discloses the usage of bacterium host cells: “The required amount, purity, homogeneity, and activity of the protein of interest usually determine the choice of expression context, vector and host. Usually the first consideration is what host cell to use. Expression in Escherichia coli is fast, inexpensive and scaleable, and minimal post-translational modifications make proteins purified from E. coli relatively homogeneous and highly desirable for structural studies.” (Hartley et al., page 359, col. 2, para. 2).
Consequently claim 14 is obvious over UniProt in view of Codon Usage Database and Hartley et al. and rejected.
Claims 11 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over UniProt entry A0A2Y9P5P3, published 9/12/2018, accessed 3/2/2026 over Codon Usage Database, https://www.kazusa.or.jp/codon/cgi-bin/showcodon.cgi?species=4932, published 6/15/2007, accessed 3/2/2026 and Hartley et al. (Hartley, James L. Current Opinion in Biotechnology 17.4: 359-366 (2006)) as applied to claim 9 above, further in view of Hokanson et al. (Hokanson, et al. Human gene therapy 14.4: 329-339 (2003)).
Regarding claim 11, claim 9 is obvious as described above. Claim 11 further recites the case wherein the vector is a plasmid vector or a viral vector. Hokanson et al. discloses the case wherein a viral vector is used: “Recombinant Adenoviral vectors have been broadly used to study the expression of genes both in vitro and in vivo and have shown promise as vectors for gene therapy and as vaccines (Russell, 2000). Adenoviral vectors are ideally suited for gene transfer because of the ease with which they can be grown, the broad targeting range to both dividing and nondividing cells, the high levels of transgene expression, and the lack of integration within the host genome.” (Hokanson et al., page 329, col. 1, para. 1).
A person of ordinary skill in the art would be motivated to use a viral vector because of the advantages listed by Hokanson and would have a reasonable expectation of success because Hokanson states they are broadly used for protein expression.
Consequently claim 11 is obvious over UniProt in view of Codon Usage Database and Hartley et al. as applied to claim 9 above, further in view of Hokanson, et al. and rejected.
Regarding claim 12, claim 11 is obvious as described above. Claim 12 further recites the case wherein the viral vector is an adeno-associated virus. Hokanson discloses: ““Recombinant Adenoviral vectors have been broadly used to study the expression of genes both in vitro and in vivo and have shown promise as vectors for gene therapy and as vaccines (Russell, 2000). Adenoviral vectors are ideally suited for gene transfer because of the ease with which they can be grown, the broad targeting range to both dividing and nondividing cells, the high levels of transgene expression, and the lack of integration within the host genome.” (Hokanson et al., page 329, col. 1, para. 1).
Consequently claim 12 is obvious over UniProt in view of Codon Usage Database and Hartley et al. as applied to claim 9 above, further in view of Hokanson, et al. and rejected.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over UniProt entry A0A2Y9P5P3, published 9/12/2018, accessed 3/2/2026 over Codon Usage Database, https://www.kazusa.or.jp/codon/cgi-bin/showcodon.cgi?species=4932, published 6/15/2007, accessed 3/2/2026 and Hartley et al. (Hartley, James L. Current Opinion in Biotechnology 17.4: 359-366 (2006)) as applied to claim 5 above, further in view of Chaudhari et al. (Chaudhari, et al. "Pharmaceutical excipients: a review." Int J Adv Pharm Biol Chem 1.1: 21-34. (2012)).
Regarding claim 15, claim 5 is obvious as described above. Claim 15 further recites a composition comprising the nucleic acid molecule of claim 5 and a pharmaceutically acceptable carrier.
Chaudhari et al. discloses various pharmaceutically acceptable carriers (Chaudhari et al., page 28, Table 1). Chaudhari also discloses: “Excipients play an important role in formulating a dosage form. These are the ingredients which along with Active Pharmaceutical Ingredients make up the dosage forms. Excipients act as protective agents, bulking agents and can also be used to improve bioavailability of drugs in some instances, the following review discusses the various types and sources of excipients along with their uses, and these can be used for different activities.” (Chaudhari et al. page 21, Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the nucleic acid molecule of UniProt, Codon Usage Database, and Hartley et al. with the excipient of Chaudhari to arrive at the claimed invention. A person of ordinary skill in the art would seek to protect or bulk the therapeutic as described by Chaudhari and would have a reasonable expectation of success because Tables 1-3 of Chaudhari provide detailed proven reason to use each excipient.
Consequently claim 15 is obvious over UniProt in view of Codon Usage Database and Hartley et al. as applied to claim 5 above, further in view of Chaudhari, et al. and rejected.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over UniProt entry A0A2Y9P5P3, published 9/12/2018, accessed 3/2/2026 over Codon Usage Database, https://www.kazusa.or.jp/codon/cgi-bin/showcodon.cgi?species=4932, published 6/15/2007, accessed 3/2/2026, Hartley et al. (Hartley, James L. Current Opinion in Biotechnology 17.4: 359-366 (2006)) and Chaudhari et al. (Chaudhari, et al. "Pharmaceutical excipients: a review." Int J Adv Pharm Biol Chem 1.1: 21-34. (2012)) as applied to claim 15 above, further in view of Baumgartner et al. (Baumgartner, Matthias R., et al. "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia." Orphanet journal of rare diseases 9.1:130 (2014)).
Regarding claim 16, claim 15 is obvious as described above. Claim 16 further recites the case wherein the composition of claim 15 further comprises one or more of L-carnitine, hydroxycobalamin, vitamin B 12, an antibiotic, sodium benzoate, N-carbamylglutamate or combinations thereof; and/or one or more of a MMUT, MMAA, MMAB, MMACHC, MMACHD, LMBRD1, MCEE, PCCA or PCCB protein or nucleic acid molecule encoding a MMUT, MMAA, MMAB, MMACHC, MMACHD, LMBRD1, MCEE, PCCA or PCCB protein.
UniProt, Codon Usage Database, Hartley et al., and Chaudhari et al. do not specifically disclose any of these additional compounds.
However, Baumgartner et al. discloses that: “Patients with a complete enzyme deficiency present in the first days to weeks of life with acute deterioration of their general clinical condition, metabolic acidosis and hyperammonemia, progressing to coma and death, if untreated. Late-onset cases of MMA and PA may present at any age, i.e. in infancy, childhood or even later with a more heterogeneous clinical picture.” (Baumgartner et al., page 2, col. 2, para. 2) and that “Chronic hyperammonemia indicates metabolic imbalance and requires investigation and treatment of the underlying cause. Sodium benzoate has been used to treat long-term hyperammonemia in MMA/PA patients.” (Baumgartner et al., page 15, col. 2, para. 5),
It would have been obvious to a person of ordinary skill in the art before the effective filing date to combine the composition of UniProt, Codon Usage Database, Hartley et al., and Chaudhari et al. to create a composition with two activities. The sodium benzoate already has a known activity in treating MMA as disclosed by Baumgartner above.
A person of ordinary skill in the art would be motivated to benefit from the activity of sodium benzoate disclosed by Baumgartner and have a reasonable expectation of success based off the disclose of Baumgartner.
Consequently, claim 16 is obvious over UniProt in view of Codon Usage Database and Hartley et al. as applied to claim 5 above, further in view of Chaudhari, et al. and rejected.
Claims Free of the Prior Art
Regarding claim 6, Uniprot Accession No: A0A2Y9P5P3 reads on claim 5 as described above. However, claim 6 claims the nucleic acid that is at least 80% identical to SEQ ID NO: 3 or SEQ ID NO: 9.
When codon usage table for Saccharomyces cerevisiae is applied to Uniprot Accession No: A0A2Y9P5P3, the resulting DNA sequence does not have 80% identity as shown below:
# Aligned_sequences: 2
# 1: EMBOSS_001
# 2: EMBOSS_001
# Matrix: EBLOSUM62
# Gap_penalty: 10.0
# Extend_penalty: 0.5
#
# Length: 930
# Identity: 661/930 (71.1%)
# Similarity: 661/930 (71.1%)
# Gaps: 0/930 ( 0.0%)
# Score: 3606.0
#
#
#=======================================
1 atgcgacctctccagattgtcccaagtcgattgatttcccagctatattg 50
||||.|||..|....|||||.|||..|.|||||.|.||.||..|.|||||
1 atgccaccattgagaattgttccatctagattgttgtctcaattgtattg 50
51 tggcctgaagcctccagcgtccacacgaaaccagatttgcctgaaaatgg 100
|||..||||.||.|||||.||.|..|.||...|.|||||..|||..||||
51 tggtttgaaaccaccagcttctattcaaactaaaatttgtttgactatgg 100
101 ctcggccaagttcaagtatggcagattttcgaaagttttttgcaaaagca 150
||.|.|||..|||...||||||.||||||.||||.|.||||||.|||||.
101 ctagaccatcttcttctatggctgattttagaaaatgttttgctaaagct 150
151 aagcacatagtcatcatctcaggagctggtgttagtgcagaaagtggtgt 200
||.||.||.||.||.||.||.||.|||||||||..|||.|||..||||||
151 aaacatattgttattatttctggtgctggtgtttctgctgaatctggtgt 200
201 tccgaccttcagaggagctggaggttattggagaagatggcaagcccagg 250
|||.||.||.|||||.|||||.||||||||||||||||||.||||.||.|
201 tccaacttttagaggtgctggtggttattggagaagatggaaagctcaag 250
251 acctggcgactcccctggcctttgcccacaacccgtcccgggtgtgggag 300
|..||||.|||||.|..||.|||||....||.||.||.|..||.|||||.
251 atttggctactccacaagcttttgctagaaatccatctcaagtttgggaa 300
301 ttctaccactaccggcgggaggtcatggggagcagggagcccaacgccgg 350
||.||.||.||..|..|.||.||..|.......|..||.||.||.||.||
301 ttttatcattatagaagagaagttgttcaatctaaagaaccaaatgctgg 350
351 gcaccgcgccatagccgagtgtgagacccggctgggcaagcagggccggc 400
.||....||.||.||.||.|||||..|..|..||||.|..||.||..|..
351 tcatttggctattgctgaatgtgaagctagattgggtagacaaggtagaa 400
401 gagtcgtggtcatcacccagaacatcgatgagctgcatcgcagggctggc 450
||||....||.||.||.||.||.||.|||||..|||||.|.|..|||||.
401 gagttactgttattactcaaaatattgatgaattgcatagaaaagctggt 450
451 accaggaaccttctggagatccatggtagcttatttaaaactcgatgtac 500
||.|..||..|..||||.||.||||||...||.|||||||||.|||||||
451 actaaaaatttgttggaaattcatggttctttgtttaaaactagatgtac 500
501 ctcttgtggagttgtggctgagaattacaagagtccaatttgtccagctt 550
.||||||||.|||||.|||||.|||||.||...|||||||||||||||||
501 ttcttgtggtgttgttgctgaaaattataaatctccaatttgtccagctt 550
551 tatcaggaaaaggtgctccagaacctggaactcaagatgccagcatccca 600
|.||.||.|||||||||||||||||.|.||||||||||||.||.||.|||
551 tgtctggtaaaggtgctccagaaccagaaactcaagatgctagaattcca 600
601 gttgagaaacttccccggtgtgaagaggcaggctgcgggggcttgctgcg 650
|||||.|||.|.||..|.||||||||.||.|..||.||.||.|||.||.|
601 gttgaaaaattgccaagatgtgaagaagctgcttgtggtggtttgttgag 650
651 acctcacgtcgtgtggtttggagaaaacctggatcctgccattctggagg 700
|||.||.||.||.||||||||.|||||..|||||||.||.|||.||||.|
651 accacatgttgtttggtttggtgaaaatttggatccagctattttggaag 700
701 aggttgacagagagctcgcccactgtgatttatgtctagtggtgggcact 750
|.|.||..|||||..|.||....||||||||.|||.|.||.||.||.|||
701 aagctggtagagaattggctttgtgtgatttgtgtttggttgttggtact 750
751 tcctctgtggtgtacccagcagccatgtttgccccccaggtggctgccag 800
||.|||||.||.||.|||||.||.||||||||.||..|.||..||||.||
751 tcttctgttgtttatccagctgctatgtttgctccagaagtttctgctag 800
801 gggcgtgccagtggctgaatttaacacggagaccaccccagctacgaaca 850
.||.||.|||||.|||||||||||.|..||..|.||.||||||.|.||.|
801 aggtgttccagttgctgaatttaatattgaagctactccagctgctaata 850
851 gattcaggtttcatttccagggaccctgtggaacgactcttcctgaagcc 900
||||.||.||||||||.||.||.||.|||||.||.|||.|.||.|||||.
851 gatttagatttcattttcaaggtccatgtggtactactttgccagaagct 900
901 cttgcctgtcatgaaaatgaaactgtttct 930
.|.||....|||||||.|||||||||||||
901 ttggctccacatgaaactgaaactgtttct 930
Consequently, claim 6 is free of the prior art.
Regarding claim 7, no prior art possesses the required quadruple arginine substation.
Consequently, claim 7 is free of the prior art.
Regarding claims 40-43, no prior art reads on these claims because no prior art has 100% identity to the claimed sequences.
Conclusion
Claims 40-43 are allowed.
Claims 5, 8-16, 19-20, 22, 25-29, 32-35, and 38 are rejected.
Claims 5, 6, 7, and 10 are objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to David Paul Bowles whose telephone number is (571)272-0919. The examiner can normally be reached Monday-Friday 8:30-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654